Pleural fibrosis is uncommon after inhalation of a non-fibrous particulate. These studies were conducted to investigate the mechanism of InP-induced pleural fibrosis and hyperplasia in male B6C3F1 mice. Mice were treated once by oropharyngeal aspiration (OA) with saline, 1, or 2 mg/kg InP. Bronchoalveolar lavage fluid (BALF) and pleural lavage fluid (PLF) were collected 1, 3, 14 and 28 days post-aspiration and analyzed for cell number, LDH activity, total protein and cytokine levels. In BALF cell numbers demonstrated a delayed increase, reaching significance at day 28. Protein and LDH were increased in a time-related manner, and complex changes in BALF cytokine levels were observed. Microscopic evaluation of lungs from mice treated with 1 mg/kg InP demonstrated early chronic active inflammation at weeks 1, 2, and 4. A pronounced pleural effusion with significantly increased cell numbers was present 28 days after oropharyngeal aspiration of InP. Cytokine analysis of day 28 PLF from InP treated mice demonstrated increased concentrations of IL-6, osteopontin, C-RP, fibrinogen, MMP-9, TIMP-1, VCAM-1, vWF and other cytokine/growth factors. Only TIMP-1 levels were changed in the PLF at earlier time points. Direct injection of InP into the pleural space did not cause the pronounced effusion observed after oropharyngeal aspiration of InP;however intrapleural injection of soluble InCl3 resulted in an immediate pleural effusion. These results suggested that pleural effects may be due to free indium and not InP particles. Pleural effusions have been shown to occur prior to pleural fibrosis caused by asbestos fibers. A chronic pleural effusion may have contributed to the pleural fibrosis, pleural proliferation and perivascular inflammation that were present in mice 14 weeks after oropharyngeal aspiration of InP.